Cellular and Molecular Effectors of Synovitis

该协作和协同计划的目的是确定迁移的中性粒细胞和巨噬细胞与驻留的滑膜成纤维细胞之间的相互作用如何导致滑膜血管翳的形成和关节破坏。初步结果已经确定了中性粒细胞和/或巨噬细胞衍生的蛋白/脂质介质，以及调节滑膜炎症的滑膜成纤维细胞粘附分子， 小鼠关节炎K/BxN模型。发现由迁移性炎性细胞产生的可溶性介质靶向驻留的滑膜成纤维细胞以重新编程滑膜结构。该计划将确定可溶性介质，其特定的表面受体和这些谱系表达的调节蛋白之间的相互作用如何促进滑膜炎症。项目1将决定如何 巨噬细胞/树突细胞中含CpG的寡脱氧核糖核苷酸和TLR 9之间的相互作用触发免疫级联反应，诱导IFN-γ的表达并抑制滑膜炎。项目2将确定嗜中性粒细胞衍生的LTB 4如何靶向滑膜成纤维细胞以促进滑膜炎。项目3将确定转录后控制机制如何调节调节滑膜炎的嗜中性粒细胞衍生的促炎和抗炎效应分子的产生。项目4将确定钙粘蛋白11，一种调节滑膜组织结构的滑膜成纤维细胞粘附分子，如何促成滑膜炎。关节炎形态学核心将提供病理样本的统一形态学分析，关节炎基因组学和生物信息学核心将有助于识别调节滑膜炎症的新基因。在这个项目中，以疾病为重点的机制研究有望深入了解炎症性关节炎的发病机制，并确定新的治疗发展目标。

The objective of this collaborative and synergistic program is to determine how interactions between immigrant neutrophils and macrophages and resident synovial fibroblasts lead to the formation of synovial pannus and joint destruction. Preliminary results have identified neutrophil and/or macrophage-derived protein/lipid mediators, and a synovial fibroblast adhesion molecule that regulate synovial inflammation in the K/BxN model of murine arthritis. Soluble mediators produced by immigrant inflammatory cells were found to target resident synovial fibroblasts to reprogram the synovial architecture. This program will determine how interactions between soluble mediators, their specific surface receptors, and regulatory proteins expressed by these lineages contribute to synovial inflammation. Project 1 will determine how interactions between CpG-containing oligodeoxyribonucleotides and TLR9 in macrophage/dendritic cells trigger an immune cascade that induces the expression of IFN-gamma and suppresses synovitis. Project 2 will determine how neutrophil-derived LTB4 targets synovial fibroblasts to promote synovitis. Project 3 will determine how post-transcriptional control mechanisms regulate the production of neutrophil-derived pro- and anti-inflammatory effector molecules that regulate synovitis. Project 4 will determine how cadherin 11, a synovial fibroblast adhesion molecule that regulates the architecture of synovial tissue, contributes to synovitis. An arthritis morphology core will provide uniform morphometric analysis of pathological samples and an arthritis genomics and bioinformatics core will facilitate the identification of novel genes that regulate synovial inflammation. The disease-focused mechanistic studies in this program promise both insight into the pathogenesis of inflammatory arthritis and identification of novel targets for therapeutic development.